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Listeria-based hepatocellular carcinoma vaccine facilitates anti-PD-1 therapy by regulating macrophage polarization

Oncogene volume 39, pages 1429–1444 (2020)Cite this article

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Abstract

Recently, patients with advanced cancers have been benefited greatly from immune checkpoint blockade immunotherapy. However, immune checkpoint blockade is still suboptimal in HCC treatment and more immune modifications are needed to achieve an efficient therapeutic goal. Here, we investigated the combined administration of a Listeria-based HCC vaccine, Lmdd-MPFG, and the anti-PD-1 immune checkpoint blockade antibody. We found that Lmdd-MPFG promoted the expression of PD-L1 in HCC cells but resensitized the tumor local T cell to respond to the anti-PD-1 immunotherapy. Mechanistically, the Lmdd-MPFG vaccine activates the NF-κB pathway in the tumor-associated macrophages (TAMs) through the TLR2 and MyD88 pathway, and recruits p62 to activate the autophagy pathway. The overall effect is skewing the TAMs from M2-polarized TAMs into the M1-polarized TAMs. Most importantly, it skewed the cytokine profiles into antitumor one in the tumor microenvironment (TME). This change restores the T-cell reactivity to the anti-PD-1 blockade. Our results suggested that Lmdd-MPFG combined with PD-1 blockade exerted synergistic antitumor effects through modifying TAMs in the TME and removing T-cell inhibitory signals, thereby providing a new potential strategy for HCC treatment.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation (Grant Number: 81772602, 9174210027 to YC, 81902780 to YY). The Qing Lan Project, the Six Talent Peaks Project (JY-018), the “333” project, Jiangsu Provincial key research development program of China (BE2018750 to YC).

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  1. These authors contributed equally: Guolong Xu, Dongju Feng, Yao Yao

Authors and Affiliations

  1. Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Guolong Xu, Dongju Feng, Peipei Li, Hong Yang & Yun Chen

  2. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Guolong Xu, Peipei Li & Yun Chen

  3. Department of Head and Neck Surgery, Research Center for Clinical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Nanjing Medical University Affiliated Cancer Hospital, Nanjing, 210018, Jiangsu, China

    Yao Yao & Yun Chen

  4. Department of Immunology, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Hua Sun

  5. Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing, 210029, Jiangsu, China

    Changxian Li

  6. Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210093, Jiangsu, China

    Runqiu Jiang & Beicheng Sun

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  1. Guolong Xu
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Contributions

YC and GLX conceived and designed the experiments. GLX and YY participated in the experiments and drafted the manuscript. XXM, CXL, RQJ, and BCS contributed to the sample collection and interpretation of the data. HY and DJF performed the statistical analysis. GLX, PPL, and HS revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yun Chen.

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Xu, G., Feng, D., Yao, Y. et al. Listeria-based hepatocellular carcinoma vaccine facilitates anti-PD-1 therapy by regulating macrophage polarization. Oncogene 39, 1429–1444 (2020). https://doi.org/10.1038/s41388-019-1072-3

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